Educación Química (2016) 27, 139---142

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HOW DOES ONE EXPERIMENT?

‘‘Green’’ Suzuki-Miyaura cross-coupling: An exciting

mini-project for chemistry undergraduate students
Bruna Pereira Vargas, Clarissa Helena Rosa, Diego da Silva Rosa, Gilber Ricardo Rosa ∗

Escola de Química e Alimentos, Universidade Federal do Rio Grande --- FURG, Campus Santo Antônio da Patrulha,
Rua Barão do Cahy, 125, Cidade Alta, CEP 95500-000, Santo Antônio da Patrulha, RS, Brazil

Received 3 August 2015; accepted 20 October 2015

Available online 13 February 2016

KEYWORDS Abstract A three-week mini-project is described for an experimental Physical Chemistry or

Suzuki-Miyaura Organic Chemistry course. The activities include synthesis of a biphenyl (4-methoxybiphenyl)
cross-coupling; via the Suzuki-Miyaura cross-coupling reaction using an adapted domestic microwave oven. The
Eco-friendly technical skills and concepts that are typically presented in practical chemistry courses are
synthesis; covered, including microwave heating, separation of mixtures, TLC techniques, melting range
Microwave heating; determination, stoichiometric calculations, and GC---MS techniques.
Chemical education All Rights Reserved © 2015 Universidad Nacional Autónoma de México, Facultad de Química.
This is an open access item distributed under the Creative Commons CC License BY-NC-ND 4.0.

PALABRAS CLAVE Acoplamiento cruzado «verde» de Suzuki-Miyaura: un mini-proyecto emocionante

Acoplamiento para estudiantes de pregrado en química
cruzado de
Suzuki-Miyaura; Resumen Un mini-proyecto de 3 semanas se describe en un curso experimental de Fisico-
Síntesis sostenible; química o Química Orgánica. Las actividades incluyen la síntesis de un bifenilo (4-metoxibifenil)
Calentamiento por a través de la reacción de acoplamiento cruzado de Suzuki-Miyaura usando un horno de microon-
microondas; das doméstico adaptado. Las habilidades técnicas y conceptos que normalmente se presentan
Enseñanza de la en los cursos de química prácticos están cubiertos, incluyendo el calentamiento por microondas,
química la separación de mezclas, técnicas de TLC, la determinación del intervalo de fusión, cálculos
estequiométricos, y las técnicas de GC-MS.
Derechos Reservados © 2015 Universidad Nacional Autónoma de México, Facultad de Química.
Este es un artículo de acceso abierto distribuido bajo los términos de la Licencia Creative
Commons CC BY-NC-ND 4.0.

∗ Corresponding author.
E-mail address: gilberrosa@furg.br (G.R. Rosa).
Peer Review under the responsibility of Universidad Nacional Autónoma de México.

http://dx.doi.org/10.1016/j.eq.2015.11.006
0187-893X/All Rights Reserved © 2015 Universidad Nacional Autónoma de México, Facultad de Química. This is an open access item distributed
under the Creative Commons CC License BY-NC-ND 4.0.
140
Introduction
Recent advances in chemistry and specifically the emer-
gence of green chemistry require that students be trained
in catalytic organic reactions (Lenardão, Freitag, Dabdoub,
Batista, & Silveira, 2003). Microwave heat, a global trend
in eco-friendly synthesis, that can be applied in chemistry
classes is very efficient and produces excellent results with a
short reaction time (Dalmás et al., 2013; Konrath, Piedade,
& Eifler-Lima, 2012; Teixeira et al., 2010). Thus, teaching
mini-projects that involve more complex organic synthe-
ses (e.g., C C cross-coupling reactions) that are prepared
using microwave heat presents a good method for a thorough
training in organic chemistry (Aktoudianakis et al., 2008;
Soares, Fernandes, Chavarria, & Borges, 2015). Therefore,
the use of microwave heat technology in organic synthesis
must be included in the training of future professionals.
To provide students with this experience, a three-week
experiment (lab period = 3 h/week) is described based on
the Suzuki-Miyaura cross-coupling reaction of phenylboronic
acid (1) with 4-iodoanisole (2), which is catalyzed by Pd/C,
to synthesize 4-methoxybiphenyl (3) via refluxing under air
in an adapted domestic microwave oven (Scheme 1; Dalmás
et al., 2013).
The primary goal of this experiment is to introduce stu-
dents to a research environment by familiarizing them with
the scientific literature and detailed laboratory procedures.
At the conclusion of the three-week mini-project, students
should be more comfortable with synthesizing organic com-
pounds via C C cross-coupling reactions, and they should
also be able to identify reaction products using current chro-
matographic techniques (TLC and GC---MS). They also learn
to report their results in a journal-ready format.
Experiment
The students work in groups of three. Prior to the initial
laboratory period, students read journal articles related to
the experiment (Aktoudianakis et al., 2008; Oliveira et al.,
2015; Soares et al., 2015). During week one, a quick intro-
duction to the microwave synthesis technique is provided.
Students synthesize compound 3 via the Suzuki-Miyaura
cross-coupling reaction that is catalyzed by Pd/C. Phenyl-
boronic acid (1.5 mmol), 4-iodoanisole (1.0 mmol), Pd/C
10 wt.% loading (15 mg, 1.4 mol% of Pd), K2 CO3 (2.0 mmol),
and 8 mL of dimethylformamide (DMF) are refluxed under air
in an adapted domestic microwave oven for an assigned time
(30, 45, 50, 60, or 90 min). After the reaction time is com-
plete, the mixture is stored under air at room temperature
until the next class.
During week two, the retention factors (Rf) of compounds
1, 2 and 3 (provided by professor) and the reaction mixture
are determined using thin layer chromatography (TLC). To
determine if the cross-coupling product forms, the students
Pd/C, microwave
B(OH) + I OMe
2
K2 CO3 , DMF
1 2
Scheme 1 Suzuki-Miyaura cross-coupling performed by students.
B.P. Vargas et al.
perform the experiment to isolate the 4-methoxybiphenyl
from initial reaction mixture.
Week three focuses on the characterization of compound
3. The students collect 4-methoxybiphenyl as white crystals
and determine its melting range and mass chromatogram
using GC---MS. The detailed procedures are in the Supporting
Information.
Results and discussion
The mini-project was implemented with 18 students in 2014
in an upper-division undergraduate course, Physical Che-
mistry II, Course Agroindustrial Engineering with an empha-
sis on agrochemistry. The course covered the basic
techniques of catalysis that are applied in organic synthe-
sis of bioactive compounds. Additionally, the mini-project
was tested with 15 students in 2014 of Technical Course in
Chemistry, discipline of Organic Chemistry III, in the Dom
Feliciano School (Gravataí --- RS, Brazil).
The students found it interesting to use an adapted
domestic microwave oven to heat the Suzuki-Miyaura
reaction mixture. This apparatus has already been used
successfully in N C cross-coupling reactions by our group
(Dalmás et al., 2013). The yield ranged from 41% to 92%
(Table 1), according to the heating time used. The low yields
of compound 3 were associated with variables related to
purification and the short reaction time. However, even
with unsatisfactory results from the reaction, a fruitful
discussion concerning the technical errors can occur. The
reported melting range of the pure 4-methoxybiphenyl is
81---83.5 ◦ C (Rosa, Rosa, Rominger, Dupont, & Monteiro,
2006). Each student group reported melting points that were
within this range (Table 1). Moreover, the students ana-
lyzed the mass chromatogram obtained for compound 3
using the GC---MS technique. Representative data from a stu-
dent group is provided in the Instructor’s Notes in Supporting
Information.
The longer reaction times resulted in higher yields.
Approximately 90 min was necessary to fully convert the
reagents to the cross-coupling product (previously tested).
Group 1 obtained a higher than expected yield after 30 min.
For this time, the conversion is low (∼45%), and we believe
the product contains traces of compound 2 (mp 50---53 ◦ C)
with 3. There were no major differences in the yield
obtained by the students in the technical course (Dom Feli-
ciano) as opposed to those in the undergraduate (FURG)
course for the reaction times of 45---60 min. However, the
data from the undergraduates were more consistent (see
Fig. 1). This shows the flexibility of the mini-project, which
can be applied to both levels of education. For 90 min, group
10 likely lost the mass of the isolated product during the
procedure.
These results were explained using the classic catalytic
cycle for the Suzuki-Miyaura cross-coupling reaction (only
OMe
3
Suzuki-Miyaura cross-coupling performed by students 141

Table 1 The results obtained for each group during the mini-project.a
Group Affiliation Time (min) Melting range (◦ C) Yield (%)
1 Dom Feliciano 30 74---76 61
2 FURG 30 81---82 41
3 Dom Feliciano 45 84---86 60
4 FURG 45 81---83 53
5 Dom Feliciano 50 82---85 52
6 FURG 50 86---88 57
7 Dom Feliciano 60 81---84 74
8 FURG 60 86---89 79
9 FURG 60 81---82 83
10 Dom Feliciano 90 84---85 78
11 FURG 90 82---85 92
a Suzuki-Miyaura cross-coupling conditions: 4-iodoanisole (1.0 mmol), phenylboronic acid (1.5 mmol), Pd/C (15 mg, 1.4 mol% of Pd),

K2 CO3 (2.0 mmol), DMF (8 mL), refluxed under air in the adapted domestic microwave oven to produce the isolated yields.

95 can also be tested as catalysts in this C C cross-coupling

90 reaction (Zim, Monteiro, & Dupont, 2000).
85
80
Conclusion
75
70
This three-week mini-project introduced students to a
Yield (%)

65
modern organic synthesis process. This study was designed
60 as a low-cost, practical class that promotes the use of mate-
55 Dom feliciano rials and reagents available in laboratories with limited
FURG
50 resources. Starting with basic information, students pre-
45 pared compound 3 via the Suzuki-Miyaura cross-coupling
40 reaction, purified it via crystallization, determined its melt-
35 ing range and obtained a mass chromatogram to confirm its
30 40 50 60 70 80 90 purity. Additionally, the students used a common procedure
Reaction time (min) in modern organic chemistry laboratories. To conclude this
mini-project, the students provided an explanation for the
Figure 1 Comparison of results obtained in the mini-project phenomenon in a laboratory report (in manuscript format).
for the different courses. The pedagogical objectives proposed for this mini-
project were fully achieved. The sequence of the related
the FURG students, Fig. 2). The adopted catalytic system activities motivated and effectively engaged all students,
is eco-friendly because of the use of microwave heat and creating a cooperative spirit between the workgroups. The
phosphine-free conditions, which are global trends in mod- students participating in similar activities exhibited out-
ern organic synthesis. Other Pd sources (commercial salts) standing performance in the research groups.

Pd/C
Conflict of interest
Ar Ar'
[Pd 0]
The authors declare no conflict of interest.
Reductive
Elimination ArI

Oxidative Acknowledgments
Ar Addition

[PdII] This work was supported by grants from CNPq (# 404601/

2013-8) and FAPERGS (# 14/0339-9) (Brazil).
Ar' Ar
[Pd II]
I Appendix A. Supplementary data
B(OH)2X.K 2CO3 Ar'B(OH)2

Transmetalation Student Handout (procedures for the synthesis and cha-

racterization of 4-methoxybiphenyl) and Instructor’s Notes.
Figure 2 Catalytic cycle of the Suzuki-Miyaura cross-coupling This material is available via the Internet in PDF file format,
reaction (Oliveira et al., 2015). free of charge.
142
Supplementary data associated with this article can
be found, in the online version, at doi:10.1016/j.eq.
2015.11.006.
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